ABSTRACT/SUMMARY ? PROJECT 1 (GILBERTSON) Pediatric cancers contain a number of recurrent gene fusions capable of initiating malignant transformation in developing tissues. The Gilbertson lab has shown that more than two-thirds of forebrain ependymomas contain chromothripsis exquisitely restricted to chromosome 11q, resulting in translocation between RELA, the principal effector of canonical NF-?B signaling, and an uncharacterized gene, C11orf95 (RELAFUS). RELA is well understood as the main effector of canonical NF-?B signalling; however, the function of C11orf95 remains unknown. The Holland and Gilbertson labs have recently shown that gene transfer of RELAFUS to nestin expressing CNS stem cells in vivo is sufficient to induce EPN. In this project we will use mouse modelling systems to determine the function of the C11orf95 gene partner in RELAFUS and the critical downstream components of signalling from it as well as the RELAFUS fusion protein. This information will ultimately lead to the development of therapeutic targets in the other projects of this grant. These data suggest the overarching hypothesis that the fusion of C11orf95 and RELA convenes a unique and aberrant biological state within a specific population of forebrain NSCs that drives aggressive ependymoma genesis, presenting a therapeutic vulnerability for new treatments.